The present invention relates to novel calixarenes, methods of their preparation, and uses thereof, in particular for the sequestration of metals.
European Patent Publication No. 0 432 989 describes a number of calixarene and oxacalixarene derivatives as having metal sequestering properties, and reviews some of the prior art in this field.
In a first aspect of the present invention there is disclosed calixarenes of the formula (I). The term calixarenes as used hereinafter is intended to embrace also oxacalixarenes, 
wherein:
L is [Cxe2x80x94CH2xe2x80x94] or [xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94] and may be the same or different between each aryl group.
R5 is H, halogen, or C1-C10 aliphatic hydrocarbyl group, C6-C20 aryl group, C6-C20 hydrocarbylaryl group, any of which may optionally be substituted by one or more halo or oxo groups or interrupted by one or more oxo groups, and R5 may be the same or different on each aryl group.
R1 comprises a carboxy group [xe2x80x94COOxe2x88x92] which may or may not be protonated or protected. Suitable protecting derivatives include salts and ester derivatives of the carboxylic acid.
two groups out of R2, R3, and R4 are H
the one group out of R2, R3, and R4 not being H comprises an amide. group
The combination of xe2x80x98acidxe2x80x99 (or protected acid) and xe2x80x98amidexe2x80x99 in the calixarenes of the present invention is not found in the calixarenes of the prior art; this combination leads to unexpected and desirable metal sequestering properties (particularly for lanthanide and actinide cations) as will be further discussed below.
Preferably:
R2 and R4 are H and R3 comprises the amide group; L is [xe2x80x94CH2xe2x80x94]xe2x80x94 between each of the aryl groups;
R5 is tertiary alkyl, especially butyl.
Preferably the carboxy group R1 conforms to the general formula (A):
[xe2x80x94Xxe2x80x94COOR10]xe2x80x83xe2x80x83(A)
wherein X is a C1, a C2 or a C3 carbon chain being a part of an aliphatic hydrocarbyl group, aryl group or hydrocarbylaryl group, any of which may optionally be substituted by one or more halo, oxo or nitro groups.
R10 is H or a protecting group being a salt or an Ester derivative. Salts include metal salts e.g. alkali (such as Li) or alkali earth metals, or ammonium or substituted ammonium derivatives. The choice of salt should be made such as to prevent the cation interfering with the operation of the calixarene in practice. Ester groups may be formed with C1-C10 aliphatic alkyl alcohols, C6-C20 aryl alcohols, C6-C20 hydrocarbylaryl alcohols, any of which may optionally be substituted by one or more halo, nitro, or oxo groups or interrupted by one or more oxo groups. Examples include benzyl, p-methoxybenzyl, benzoylmethyl, p-nitrobenzyl, methyl, ethyl, butyl, t-butyl etc.
More preferably R1 is of the general formula (B):
[xe2x80x94(C.R6.R7)axe2x80x94COOR10]xe2x80x83xe2x80x83(B)
wherein n is 1, 2 or 3 and R6 and R7 are H or halogen and can be the same or different on each carbon.
Alternatively R1 may be of the general formula (C): 
wherein n is 0 or 1 and R6 and R7 are H or halogen and can be the same or different on each carbon and wherein the phenyl ring of the benzoic acid group may be optionally substituted by one or more halo, oxo or nitro groups.
In each case it is preferable that a is 1 and R6, R7 and R10 are all H.
In unprotected acid embodiments, preferably the aliphatic hydrocarbyl group, aryl group or hydrocarbylaryl group of X in formula (A) are substituted by one or more groups which cause a reduction in the pKa of the carboxy group with respect to the unsubstituted molecule e.g. nitro.
For instance the phenyl ring of the benzoic acid of formula (C) is preferably substituted by one or more groups which cause a reduction in the pKa of the carboxy group with respect to the unsubstituted molecule e.g. nitro.
Preferably the amide group R2, R3, or R4 of formula (I) is of the general formula (D): 
wherein n is 1, 2 or 3 and R6 and R7 are H, halogen, or C1-C10 aliphatic hydrocarbyl group, and can be the same or different on each carbon, and wherein R8 and R9, which may be the same or different, are H or C1-C10 aliphatic hydrocarbyl group (optionally halo substituted) including a cycloaliphatic ring formed by R8 and R9 together.
In certain embodiments of the invention, as described in more detail below, R8 or R9 may form a bridge to between a calixarene of the present investigation and a further calixarene in order to produce a dimer.
Most preferably, the calixarene is of the formula (II): 
(5,11,17,23-tetra-tert-butyl-25-[hydroxycarbomylmethoxy]-27-[(N-diethylamino) carbomylmethoxy]-26-28-dihydroxy-calix[4]arene.)
This compound (xe2x80x9cacid-amidexe2x80x9d) has been found to be useful for the extraction of both divalent and trivalent metal ions such as Pb, Sr, Hg, Bi and Y; in particular Lanthanides (e.g. La) and Actinides (e.g. U).
Also embraced by the present invention are calixarenes of the general formulae (I) and (II) but wherein some or all of phenyl groups of the calixarene ring are further peripherally substituted in such a way as not to compromise the advantageous combination of the carboxy and amide groups which form the central core of the present invention. Possible substituents include halogen, nitro, C1-C10 aliphatic hydrocarbyl group, C6-C20 aryl group, or C6-C20 hydrocarbylaryl group, any of which may optionally be substituted by one or more halo or oxo groups or interrupted by one or more oxo groups. Indeed certain substituents (e.g. nitro) may be desirable in as much as they reduce the pKa values of the two hydroxy groups of the calixarene ring, thereby modifying the metal-chelating properties of the compound.
In a second aspect of the present invention there is disclosed a method of sequestering metals comprising contacting the metals with a calixarene as described above.
Preferably the calixarene is used to complex metals at a pH of 2-6, (most preferably pH 3-6) since at higher pHs there is an increased risk of the target metal precipitating. For instance, precipitation of Lanthanides occurs at fairly low pH (7.5 for La, 6.4 for Lu).
If required, additional complexing agents (such as are well known to the skilled person) may be used to prevent precipitation of target metals. This allows the use of the calixarene at higher pHs, which will advantageously reduce protonation of the carboxy and hydroxy groups. The use of such additional complexing agents can thus raise the useful working pH range of the calixarene to the point at which the metal-calixarene complex itself an precipitates e.g. around pH 11.
The use of higher pHs (e.g. pH 7 to 10, preferably pH 9) may be particularly advantageous for increasing the concentration of negative charge in calixarenes having protected acid groups or in calixarene-dimers, which may otherwise be reduced by the protecting group or steric effects respectively.
If desired the environmental pH may be adjusted using conventional methods of the art. For instance if it is desired to raise the pH, then LiOH may be added. If desired, the pH may be buffered by using an appropriate buffer such as are well known to those skilled in this art eg. citrate.
In all cases the lower pH limit of useful operation will be dependent on the pKa of each chelating group in the calixarene, since that will dictate whether each (unprotected) carboxy or hydroxy group will be protonated at any given pH. It may therefore be desirable for each group to have a low pKa e.g. when treating acidic waste streams for which the pH cannot be readily adjusted. The pKa of the protonated carboxy and the amide group of the calixarene of formula (II) is less than 3.
Preferably the calixarene is dissolved in a hydrophobic organic solvent (e.g. dichloromethane) and this is mixed with an aqueous phase containing metal ions (e.g. in equal volumes).
The phases are then stirred or otherwise agitated, typically for around 1 hour, followed by a 2 hour separation time.
Preferably the calixarene is present in excess over the metal target e.g. 25-fold, or 250-fold. The excess required for useful extraction will depend on the nature of the metal target e.g. size, charge etc.
Preferably the metal target is U, Hg, Am, Pb, Sr, Bi, or Y for instance in methods of environmental clean up. Alternatively the metal could be an actinide such as Am or another lanthanide.
The calixarenes described above are such that the metal complexes formed with the target ion may be overall neutral without the necessity for additional counter-anions. A further advantage is that the calixarenes can be highly selective, thereby preventing unwanted metal ions complexing all available sites.
A still further advantage of the methods of the current invention is that the extracted metal ions can be recovered following sequestration into the hydrophobic phase simply by contacting that phase with a relatively small (with respect to the original metal-containing sample) volume of acid (e.g. 1 M) thereby causing the pH to drop and the metal to become decomplexed and enter the acid aqueous phase. The calixarene can then be reused simply by evaporation of the solvent.
Alternatively, the extracted metal ions can be recovered following extraction simply by evaporating the solvent to leave the metal-calixarene complex.
Thus in preferred forms, e.g. using the xe2x80x98acid-amidexe2x80x99 above, the extraction methods of the present invention are both selective and efficient and do not require additional ions to operate. The nature of the extraction can be readily optimised by adjustment of the pH.
In a third aspect of the invention there is disclosed a solid phase-bound calixarene of the type described above e.g. polymer bound. For instance the calixarene may be physisorbed and immobilised onto polystyrene divinyl benzene beads. Immobilisation of the calixarene on a solid phase support may assist in the extraction methods of the invention. The preparation of such bound calixarenes would present no undue burden to those skilled in the art, in the light of the present disclosure in conjunction with the methods, or methods analogous to the methods, described by Harris et al. in U.S. Pat. No. 4,642,362 or 4,699,966, or Parker in U.S. Pat. No. 4,447,585 or Tetrahedron 36 461-510 (1980), or in European Patent Publication No. 0 217 656.
In a fourth aspect of the invention there is disclosed a process for preparing the calixarenes described above. Intermediates for use in the process form a fifth aspect of the invention.
In a sixth aspect of the invention there is disclosed a calixarene dimer comprising two calixarenes of formula (I) wherein the amide group of each is of the general formula (D) above, and wherein the R8 or R9 group of one calixarene is conjugated to the R8 or R9 of the other calixarene, optionally through a spacer group R11 as shown schematically in formula (III): 
The optional spacer group R11 may be C1-C6 aliphatic hydrocarbyl group, C6-C10 aryl group, C6-C16 hydrocarbylaryl group, any of which may optionally be substituted by one or more halo or oxo groups or interrupted by one or more oxo groups. In the absence of a spacer group the R8 or R9 group of one calixarene is conjugated directly to the R8 or R9 group of the other. In any case it is preferable that there is only 1, 2, 3 or 4 bridging atoms (preferably carbon atoms) between the Nitrogen atoms of the two amide groups. Most preferably there is 2 or 3 bridging carbon atoms. As described in more detail below, this spacing between the calixarenes may help to pre-stress the dimer into a particular stable, low-energy, chelating conformation, and thereby enhancing the specificity for target metals with respect to calixarene monomers. groups or interrupted by one or more oxo groups. In the absence of a spacer group the R8 or R9 group of one calixarene is conjugated directly to the R8 or R9 group of the other. In any case it is preferable that there is only 1, 2, 3 or 4 bridging atoms (preferably carbon atoms) between the Nitrogen atoms of the two amide groups. Most preferably there is 2 or 3 bridging carbon atoms. As described in more detail below, this spacing between the calixarenes may help to pre-stress the dimer into a particular stable, low energy, chelating conformation, and thereby enhancing the specificity for target metals with respect to calixarene monomers.
In a further aspect of the invention there is disclosed a calixarene of formula (IV): 
wherein:
L is [xe2x80x94CH2xe2x80x94] or [xe2x80x94Oxe2x80x94CH2Oxe2x80x94] and is the same or different between each aryl group; R5 is halogen, or is a C1-C10 aliphatic hydrocarbyl group, C6-C20 aryl group or a C6-C20 hydrocarbylaryl group, any of which is optionally substituted by one or more halo or oxo or is interrupted by one or more oxo groups, and R5 is the same or different on each aryl group;
R1 is a carboxy group which is or is not protonated or protected; two groups out of R2, R3 and R4 are H; and
the one group out of R2, R3 and R4 which is not H is a thioamide group.
In a preferred embodiment R2 and R4 are H, R5 is the same on each aryl group and is a 
Alternatively, R2 and R4 are H, R5 is the same on each aryl group and is a tertiary 
In another embodiment of the invention there is disclosed a method for preparing the calixarenes of formula (IV) above.
Furthermore, there is described a method for the sequestration of metals comprising contacting the metals with a calixarene of formula (IV) as described above.